Growth hormone releasing hormone (GHRH) is a hypothalamic hormone that acts at a pituitary receptor to stimulate the pulsatile release of GH. In mammals, GH is required for normal growth and development in the young, and has continuing importance in adults affecting such diverse functions as muscle maintenance, fat deposition, skin thickness, wound healing and exercise performance. GHRH also has direct effects on sleep. These actions have widespread clinical implications not only when considering GH deficiency syndromes, but also the sharply diminished GH levels that occur with aging and obesity. The anabolic and anticatabolic activities of GH have also recently been shown to ameliorate the muscle wasting and weight loss seen with AIDS.
GHRH and other regulators of the GH axis also have great potential in agricultural applications because they can stimulate growth and improve the efficiency of feed utilization. They control the relative partitioning of nutrients between muscle and fat and so may allow the production of leaner livestock and higher yields of milk, hair and feathers.
In birds, the function and regulation of GH are not well understood and thyroid releasing hormone (TRH) as well as gonadotropin releasing hormone (GnRH) appear to be a major factors in GH release. Research studies have been inconclusive as to the physiological role of GHRH in birds. A putative chicken GHRH polypeptide has been cloned and synthesized but found to have little or no GH releasing activity at chicken pituitary cells or in live chickens. Despite this, chicken pituitaries and live chickens do respond to mammalian GHRH with GH release. Studies in chickens using mammalian GHRH have not been successful in improving growth. Thus, it has been speculated that chickens have no functional GHRH receptor.
Furthermore, Southern blot analysis, using a human GHRH receptor probe and genomic DNA from human, monkey, rat, mouse, dog, cow, rabbit, chicken and yeast, detected GHRH receptors in all mammals tested, but not in chicken or yeast. These results indicate that GHRH receptors are well conserved in all the mammals tested, but absent or less well conserved in the chicken. Binding of human GHRH to chicken pituitary membranes suggests a high affinity G protein coupled receptor for GHRH is present in chicken. A similar experiment using the putative chicken GHRH and chicken pituitary membranes detected no specific binding. Thus the function of GHRH in birds is not understood and this prevents the development of its agricultural applications.
Further investigation of GHRH's role in avian development required the isolation of the corresponding GHRH receptor (GHRH-R). Purification of pituitary receptors is very difficult because of the scarcity of tissue, problems involving the solubilization of the receptors in active form, and in developing an efficient purification method. Therefore a need exists for the isolation of the gene that encodes the GHRH-R (or biologically active fragments thereof) to allow for the large scale production of GHRH-R. There is also a need for a vector, host cell, or host organisms comprising a nucleic acid sequence encoding protein or polypeptides having the activity of GHRH-R.
Large scale production of the cloned chicken GHRH receptor would enable the screening of large numbers of GHRH analogs for identification of improved agonists and antagonists. Such agonists and antagonists will have utility in improving feed utilization and enhancing the efficient production of larger, leaner chickens and other avian species used for meat production.